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Pain pharma
- 1. PHARMACOLOGICAL ASPECTS OF PAIN MANAGEMENT DR.SOURAV CHAKRABARTY, (1ST YR PGT),DEPT OF PHARMACOLOGY, B.S.MEDICAL COLLEGE
- 2. “But pain is a perfect misery The worst of evils Excessive overturns All patience” John Milton In Paradise Lost
- 3. What is Pain? • Medical Definition “Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage” • Operative Definition “Pain is whatever the experiencing person says it is, existing whenever he/she says it does.”
- 4. . • Basically a protective mechanism. • It guides physician to the actual tissue damaging process. • Pain management should be rapid & effective, simultaneously associated with treatment of the condition that leads to pain. • So our motto is NOT TO KILL THE PAIN BUT TO HEAL THE PAIN…………..
- 5. Types of Pain ‘Nociceptive’ • Normal physiology • Beneficial • Treated with conventional analgesics (NSAID, acetaminophen, opioids) • If Unrelieved, it becomes deleterious ‘Neuropathic’ • Aberrant physiology • Poor quality of life • Difficult to treat
- 6. Normal Pain Pathways Tissue injury • Histamine • Bradykinin •Prostaglandin. Primary Afferent Lateral spino-thalamic tract
- 7. Normal Pain Pathways PAG (periaqueductal gray) Raphe Nuclei locus ceruleus Enkephalin-containing interneuron
- 8. Opioids (m, d, k) NSAIDs Local anaesthatics (voltage gated Na+ channels)
- 9. Analgesic at different level Sites of Action Medications Peripherally (at the nociceptor) Cannabinoids, NSAIDs, Opioids, Tramadol, Vanilloid receptor antagonists(i.e., capsaicin) Peripherally (along the nociceptive nerve) Local anesthetics, Anticonvulsants (except the gabapentinoids) Centrally (various parts of the brain) Acetaminophen Anticonvulsants (except the gabapentinoids), Cannabinoids. Opioids, Tramadol Descending Inhibitory pathway in the spinal cord Cannabinoids, Opioids, Tramadol, Tricyclic antidepressants, SNRIs Dorsal horn of the spinal cord Anticonvulsants, Cannabinoids, Gabapentinoids, NMDA receptor antagonists, Opioids,. Tramadol, Tricyclic antidepressants, SNRIs
- 10. Classification of drugs (Opiates): Agonist: oMorphine agonist: oMorphine oHydromorphone oOxymorphone oLevorphanol oCodeine oHydrocodone oOxycodone oMeperidine agonists: oMeperidine oFentanyl. o Methadone agonists: oMethadone oPropoxyphene.
- 11. oMixed agonist-antagonist o Pentazocine o Butorphanol o Nalbuphine o Buprenorphine o Dezocine o Antagonists: o Naloxone o Central analgesics: o Tramadol o Tapendalol
- 12. Non-opiates NSAIDS A- nonselective COX inhibitors (conventional nsaids) • Salicylates: aspirin, diflunisal. • Pyrazolone derivatives: phenylbutazone, oxyphenbutazone. • Indole derivatives: indomethacin, sulindac. • Propionic acid derivatives: ibuprofen, naproxen, ketoprofen, flurbiprofen. • Anthranilic acid derivative: mephenamic acid. • Aryl-acetic acid derivatives: diclofenac. • Oxicam derivatives: piroxicarn, tenoxicam. • Pyrrole-pyrrole derivative: ketorolac.
- 13. B- Preferential COX-2 inhibitors Nimesulide, Meloxicam, Nabumetone C- Selective COX-2 inhibitors Celecoxib, Rofecoxib, Valdecoxib D- Analgesic- antipyretics with poor antiinflammatory action Paraaminophenol derivative: Paracetamol (Acetaminophen). Pyrazolone derivatives: Metamizol (Dipyrone), Propiphenazone. Benzoxazocine derivative: Nefopam.
- 14. • Anticonvulsants –Gabapentin –Pregabalin –Phenytoin –Carbamazapine –Oxcarbamazapine –Clonazepam • Antidepressants –Doxepine –Amitriptyline –Imipramine –Nortriptyline –Desipramine –Venlafaxine –Duloxetine
- 15. • Local anaesthetics: o Esters: o Procaine o Chlorprocaine o Tetracaine o Amides: o Bupivacaine. o Mepivacaine. o Ropivacaine o Prilocaine o Etidocaine • Muscle relaxant o Smooth muscle relaxants o Hyoscine butylbromide o Dicylomine o Oxybutrinine o Darifenacine o Solifenacine o Flavoxate o Skeletal muscle relaxants o Baclofen o Thiocolchicoside o Chlorzoxazone o Diazepam o Mephenesine
- 16. Opioids • "Among the remedies which it has pleased Almighty God to give to man to relieve his sufferings, none is so universal and so efficacious as opium.“ • Sydenham, 1680
- 17. . The term opioid refers broadly to all compounds related to opium. The word opium is derived from opos, the Greek word for "juice," the drug being derived from the juice of the opium poppy, Papaver somniferum.
- 18. Endogenous Opoid Peptides OPIOID RECEPTOR CLASS EFFECTS ASSOCIATED ENDOGENOUS ENDORPHIN Mu 1 Euphoria, supraspinal analgesia, confusion, dizziness, nausea, low addiction potential Endormorphin 1,2=Beta-endorphin >Enkephalin=Dynorphin Mu 2 Respiratory depression, CVS and GI effects, miosis, urinary retention Beta-endorphin=Endormorphin 1,2>Enkephalin=Dynorphin Delta Spinal analgesia,Opioid renforcement CVS depression, decreased brain and myocardial oxygen Demand Enkephalin=Beta-endorphin>Dynorphin Kappa Supraspinal,Spinal ,Peripheral analgesia, dysphoria, psychomimetic effects, feedback inhibition of endorphin system Dynorphin A=beta-endorphin> Enkephalin
- 20. Spinal sites of opioid action. reduce transmitter release from presynaptic terminals of nociceptive primary afferents hyperpolarize second-order pain transmission neurons by increasing K+ conductance, evoking an inhibitory postsynaptic potential
- 21. Analgesic features of morphine Efficacy: • Morphine is a strong analgesic. • Higher doses can mitigate even severe pain • Degree of analgesia increasing with dose. • Simultaneous action at spinal and supraspinal sites greatly amplifies the analgesic action. Selectivity: • Suppression of pain perception is selective • No affect on other sensations • proportionate generalized CNS depression (contrast general anaesthetics).
- 22. • Type of pain: • Dull, visceral pain > sharply defined somatic pain. • Nociceptive pain>neuritic pain. • Mood & subjective effects: • Mood changes, euphoria, tranquility, mental clouding, drowsiness, indifference to surroundings as well as to our body. • Morphine has a calming effect.
- 23. OTHER CNS EFFECTS • Effects on the Hypothalamus:Body temperature usually falls slightly. .Neuroendocrine Effects. • GnRH,CRH, LH,FSH,ACTH,Testosteron,Cortisol. • Prolactin. • Miosis • Convulsion
- 24. EFFECTS ON OTHER SYSTEMS • Respiratory depression. ( Responsiveness of the brainstem respiratory centers to carbon dioxide) • Cough. • Nausea • Peripheral vasodilatation, reduced peripheral resistance, and an inhibition of baroreceptor reflexes. • Gastric motility. • Biliary, pancreatic, and intestinal secretions and delays digestion of food in the small intestine. • Constipation. • Immunosupression. • Bronchoconstriction • Uterus may be relaxed • Mild hyperglycemia due to central sympathetic stimulation . • Weak anticholinesterase action
- 25. Tolerance Onset • Develops rapidly and can be detected within 12 – 14 hours of morphine administration . • within 3 days the equianalgesic dose is increased 5 fold • Mainly developes to depressant effects NOT to stimulant effects. • Two proposed mechanisms – upregulation of cAMP system – Downregulation of μ receptors • uncoupling between μ receptor and G proteins Reversal of second messenger (cAMP) and ion channel system • Blocked by NMDA antagonists and nitric oxide synthase inhibitors.
- 26. Degrees of Tolerance High Moderate Minimal or None Analgesia Bradycardia Miosis Euphoria, dysphoria Constipation Mental clouding Convulsions Sedation Respiratory depression Antidiuresis Nausea and vomiting Cough suppression
- 27. Dependence Two components • Physical dependence: Withdrawal symptoms – sweating ,lacrimation, dehydration , – Fear, anxiety , restlessness – Mydriasis , tremor , colic – Hypertension , tachycardia, weight loss. Methadone is used to relieve withdrawal syndrome. • Psychological dependence: – Associated with craving, lasting for months or years. – Opioids facilitate DA transmission in mesolimbic /mesocortical pathways and activate endogenous reward pathways in brain.
- 28. Pharmacokinetics • Modestly absorbed from the GI tract t1/2 of morphine is ~2 hours. • Metabolised as Morphine-6-glucuronide • Excreted by the kidney • Satisfactory analgesia in cancer patients is associated with a very broad range of steady-state concentrations of morphine in plasma (16-364 ng). POTENT ANALGESIC
- 29. Routes of administration IV Plasma Concentration po / pr SC/IM 0 Half life time
- 30. Dosing formulation Liposome-encapsulated extended release morphine • –Single epidural injection lasting 48h • –S/E –vomiting, pruritus, O2 desaturation Intranasal opioid aerosols • –Fentanyl, Morphine • –Breath activated nebuliser • –Rapid onset, deep-lung dosing • –Variable bioavailability DepoFoam™Particle(diam eter: 15 microns) The non-concentric vesicles are surrounded by a lipid membrane, and each contains an internal aqueous chamber with morphine sulfate solution
- 31. Oxycodone • Semi-synthetic derivative synthesized from Thebaine • κ-opioid agonist • After a dose of conventional oral oxycodone, peak plasma levels of the drug are attained in about one hour • Oxycodone is metabolized to α and β oxycodone The oral bioavailability is 60% to 87% • t ½ -4.5 hours • mainly excreted in the urine and sweat • Dependence, addiction and withdrawal. • Oral/iv 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, and 80 mg • Controlled release
- 32. Fentanyl and Congeners • Synthetic opioid related to the phenylpiperidines • Extremely potent analgesics • Very short duration of action • Pharmacological action • Rigidity • Respiratory depression : onset is more rapid. . • Neuroexcitation • Do not release histamine . • Direct depressant effects on the myocardium are minimal. • Pharmacokinetics • Highly lipid soluble and rapidly cross the blood-brain barrier. • t1/2, 3-4 hours. Fentanyl and sufentanil • Hepatic metabolism and renal excretion. • Higher doses/ prolonged infusions- these clearance mechanisms become progressively saturated. Sufentanil Remifentanil Alfentanil
- 33. Fentanyl and Congeners(contd) • Ramifentanyl • t1/2 of 8-20 minutes • metabolized by plasma esterases • Elimination is independent of hepatic metabolism or renal excretion • Remifentanil acid, has 0.05-0.025% of the potency of the parent compound, and is excreted renally. • Short, painful procedures that require intense analgesia and blunting of stress responses • Continuous IV infusion • Short duration of action makes bolus administration impractical • Not used intraspinally • Therapeutic Uses • 1. Postoperative pain management, • 2.Labor analgesia • 3.Chronic pain treatment
- 34. Iontophoresis transdermal system Electrotransport delivery platform technology (E-TRANS/IONSYS) • Hydrogel reservoir into the skin • Low-intensity direct current • Bolus dose 40 ug • Dose interval 10 min • Upto 24 hours or a maximum of 80 doses • Audible beep & LED light indicator Transdermal patches - sustained release of fentanyl for 48-72hrs Trans buccal absorption by the use of buccal tablets, soluble buccal film, and lollypop-like lozenges permits rapid absorption,
- 35. Meperidine • Synthetic opioid. • Biotransformed by liver to Normeperidine, it is potentially neurotoxic metabolite. • Half life is 3 hr. • Accumulation of normeperidine can precipitate tremulousness, myoclonus & Seizures. • C/I in patients receiving MAO inhibitors. Methadone Synthetic opioid. Long acting MOR.Broad spectrum opioid μ receptor agonist. NMDA antagonist. Inhibitors of Monoamine transmitter reuptake. Exactly identical pharmacodynamics as that of Morphine in equi-analgesic doses. Opioid rotation is done to restore analgesic sensitivity in highly tolerant patient.
- 36. Pentazocine -κ1 agonist -Produces Spinal level analgesia • Less sedation,drowsiness &respiratory depression. Due to σ stimulation it causes – Dysphoria, hallucinations, diaphoresis & psychotomimetic effects – Increases BP/ HR/ pulmonary artery pressure • Indicated in post operative pain, moderately severe pain in burns, trauma, fractures etc • Tablets available in fixed-dose combinations with acetaminophen or naloxone combination weak antagonist or partial agonist at opioid receptors.
- 37. Tramadol Synthetic codeine analog. Weak MOR agonist 1. Produces antinociception via predominantly, a mu-opioid receptor mechanism. 2. No respiratory depression, sedation, or constipation, as observed with other opiates. 3. No analgesic tolerance 4. No psychological dependence or euphoric effects in long-term clinical trials 1. Novel mechanism of analgesic action is partially due to its adrenergic action 2. Enhanced secretion of serotonin and inhibits the reuptake of serotonin in the CNS OPIOD ACTIVITY Monoaminergic Activity
- 38. Pharmacokinetics 1. Effective and well-tolerated analgesic in all 3 forms of administration 2. PO,IV,PR 3. Onset of analgesia is within 30 minutes. 4. Duration of action from 3 to 7 hours 5. Drowsiness - most frequent side effect 6. Transformation by the cytochrome P450 complex to the metabolically active O-desmethyl- tramadol Withdrawal symptoms after abrupt discontinuation or reduction of dose Dependence Serotonin Syndrome
- 39. Tapentadol Centrally acting analgesic with 2 mechanisms of action in a single molecule: • mu-opioid agonism • norepinephrine reuptake inhibition • four stereoisomers .RR, SS,RS and SR forms and RR form - approved as analgesic. Oral absorption rapid • Crosses the blood–brain barrier; a rapid onset of action • t ½ = 4hrs Is present in the serum in the form of conjugated metabolites Excretion was exclusively renal FDA approved tapentadol in 2008 moderate-to-severe acute pain in patients older than 18 years
- 40. Opiod antagonist • Naloxone,Naltrexone, Nalmefene. • Small doses (0.4 to 0.8 mg) i.m. or i.v. prevent or promptly reverse the effects of Mu receptor agonists. • In morphine dependent ,small s.c doses of naloxone (0.5 mg) precipitate a moderate-to-severe withdrawal syndrome. • In the neonate, the initial dose is 10 microgm/kg given intravenously, intramuscularly, or subcutaneously.
- 41. Therapeutic uses of opiods • Analgesia • Acute pulmonary edema • Cough • Diarrhea • Shivering • Applications in anesthesia. Sir William Osler called morphine "God's own medicine."
- 42. APPROXIMATE EQUI-ANALGESIC APPROXIMATE EQUI-ANALGESIC RECOMMENDED STARTING DOSE (adults > 50 kg) DRUG ORAL DOSE PARENTERAL DOSE ORAL PARENTERAL Opioid Agnoists Morphine 30 mg q3-4h (around-the- clock dosing) 60 mg q3-4h (single dose or intermittent dosing) 10 mg q3-4h 15 mg q3-4h 5 mg q3-4h Codeine 130 mg q3-4h 75 mg q3-4h 30 mg q3-4h 30 mg q2h (1M/SC) Hydrocodone 7.5 mg q3-4h 1.5 mg q3-4h 4 mg q3-4h 1 mg q3-4h Hydrocodone ( typically with acetominophen) 30 mg q3-4h Not available 5 mg q3-4h Not available Levorphanol 4 mg q6-8h 2 mg q6-8h 2 mg q3-4h 1 mg q6-8h Meperidine 300 mg q2-3h 100 mg q3h Not recommended 50 mg q3h Methadone 20 mg q6-8h 10 mg q6-8h 2.5 mg q12h 2.5 mg q12h Oxycodone 30 mg q3-4h Not available 5 mg q3-4h Not available Oxymorphone Not available 1 mg q3-4h Not available 1 mg q3-4h Propoxyphene 130 mg Not available 65 mg q4-6h Not available Tramadol 100 mg 100 mg 50-100 mg q6h 50-100 mg q6h
- 43. Patient Controlled Analgesia (PCA)
- 44. PCA Self adminastration of opiod agonist by parenteral route. • Fentanyl is the preferred opioid in most circumstances. • Morphine or hydromorphone are alternative choices. • One hr max dose :Max amount of drug that PCA pump will deliver in 1 hour • Continuous infusion • Morphine 0.075 mg/kg • Fentanyl 0.75 mcg/kg • Freedom to self assess the need to push a tailored dose of an opiod • Paradoxically less dependance.
- 45. Adverse Effects of the Opioid Analgesics Behavioral restlessness, tremulousness, hyperactivity (in dysphoric reactions) Respiratory depression Nausea and vomiting Increased intracranial pressure Postural hypotension accentuated by hypovolemia Constipation Urinary retention Itching around nose, urticaria (more frequent with parenteral and spinal administration)
- 46. Precautions H5B3 conditions. • Hypotension • Hepatic damage • Hypertrophy of prostate • Head injury • Hypothyroidism • Bronchial asthma • Biliary colic • Babies 1. Not with corticosteriod as it increases immunosupression. 2. Partial agonist + pure agonist=severe withdrawal symptoms. 3. Not with MAO inhibitors. 4. Not with sedatives.
- 47. NMDA antagonists • Memantine • Amantadine • Ketamine
- 48. Indications • Windup pain • Opioid tolerance • Opioid induced hyperalgesia • Pain threshhold reduction • Longterm potentiation
- 49. Ketamine • A congener of phencyclidine Non-competitive glutamate NMDA receptor antagonist. • At low doses, the analgesia effects of ketamine are mediated by antagonism on the NMDA receptors. • Management of moderate to severe pain. • Used in conjunction with opioids • Norketamine, rapid clearance, large Vd The ketamine-induced cataleptic state - nystagmus with pupillary dilation, salivation, lacrimation.
- 50. References • Basic & Clinical Pharmacology,Katzung(12th edition),2012. • Goodman & Gilman’s the pharmacological basis of therapeutics(12th),2011 • Pharmacotherapy Hand book(6th edition),B.Wells.
- 51. THANK YOU For listening…….
Editor's Notes
- It does this by detecting, localizing, and identifying potential or actual tissue-damaging processes. Because different diseases produce characteristic patterns of tissue damage, the quality, time course, and location of a patient's pain complaint provide important diagnostic clues. It is the physician's responsibility to provide rapid and effective pain relief to the patient,which must be simultaneously associated with early diagnosis & prompt treatment of the condition which leads to that pain.
- the drug still is obtained from opium or extracted from poppy straw. Opium is obtained from the unripe seed capsules of the poppy plant, Papaver somniferum. The milky juice is dried and powdered to make powdered opium, which contains a number of alkaloids. Only a few¾morphine, codeine, and papaverine¾have clinical usefulness. The first undisputed reference to opium is found in the writings of Theophrastus in the third century B.C. Arab traders introduced the drug to the Orient, where it was employed mainly for the control of dysenteries. In 1680, Sydenham wrote: "Among the remedies which it has pleased Almighty God to give to man to relieve his sufferings, none is so universal and so efficacious as opium." In 1806, Serturner reported the isolation of a pure substance in opium that he named morphine, after Morpheus, the Greek god of dreams. In 1975, Hughes and associates identified an endogenous opiate-like factor that they called enkephalin (from the head). Soon after, two more classes of endogenous opioid peptides were isolated, the dynorphins and endorphins
- Top left: Schematic of organization of opiate action in the periaqueductal gray. Top right: Opiate-sensitive pathways in PAG Mu opiate actions block the release of GABA from tonically active systems that otherwise regulate the projections to the medulla (1) leading to an activation of PAG outflow resulting and activation of forebrain (2) and spinal (3) monoamine receptors that regulate spinal cord projections (4) which provide sensory input to higher centers and mood. Bottom left: Schematic of primary afferent synapse with second order dorsal horn spinal neuron, showing pre- and post-synaptic opiate receptors coupled to Ca2+ and K+ channels, respectively. Opiate receptor binding is highly expressed in the superficial spinal dorsal horn (substantia gelatinosa). These receptors are located presynaptically on the terminals of small primary afferents (C fibers) and postsynaptially on second order neurons. Presynaptically, activation of MOR blocks the opening of the voltage sensitve Ca2+ channel, which otherwise initiates transmitter release. Postsynaptically, MOR activation enhances opening of K+ channels, leading to hyperpolarization. Thus, an opiate agonist acting at these sites jointly serves to attenuate the afferent-evoked excitation of the second order neuron.
- The opioids have two well-established direct G protein-coupled actions on neurons: (1) they close voltage-gated Ca2+ channels on presynaptic nerve terminals and thereby reduce transmitter release, and (2) they hyperpolarize and thus inhibit postsynaptic neurons by opening K+ channels.
- The associated reactions to intense pain apprehension, fear, autonomic effects are also depressed. Perception of pain and reaction to it are both altered so that pain is no longer as unpleasant or distressing, i.e. patient tolerates pain better. Other effects include feeling of detachment, Lack of initiative, limbs feel heavy and body warm, mental clouding and inability to concentrate. In normal people, in the absence of pain or apprehension, these are generally appreciated as unpleasant Patients in pain or anxiety and addicts specially perceive it as pleasurable Refer it as 'high'. Rapid IV injection by addicts - gives them a 'kick' or 'rush' which is intense, pleasurable—akin to orgasm. Thus one has to learn to perceive the euphoric effect of morphine.
- Opioids alter the equilibrium point of the hypothalamic heat-regulatory mechanisms such that body temperature usually falls slightly. Morphine-like opioids depress respiration at least in part by virtue of a direct effect on the brainstem respiratory centers. when opioids are administered parenterally to women within 2 to 4 hours of delivery, which can lead to transient respiratory depression in the neonate because of transplacental passage of opioids. Opioids also depress the pontine and medullary centers involved in regulating respiratory rhythmicity and the responsiveness of medullary respiratory centers to electrical stimulation. NAUSEA due to direcet stimulation of the chemoreceptor trigger zone for emesis in the area postrema of the medulla.
- The tolerance is not pharmacokinetic but due to the true cellular adaptive response . Thus, analgesic action of morphine can be dissociated from tolerance and dependence which contribute to its abuse by NMDA receptor antagonists Agents that recouple μ receptor and G proteins
- of a given dose is less after oral than after parenteral administration because of variable but significant first-pass metabolism in the liver. For example, the bioavailability of oral preparations of morphine is only ~25%. The shape of the time-effect curve also varies with the route of administration, so the duration of action often is somewhat longer with the oral route. If adjustment is made for variability of first-pass metabolism and clearance, adequate relief of pain can be achieved with oral administration of morphine. Satisfactory analgesia in cancer patients is associated with a very broad range of steady-state concentrations of morphine in plasma (16-364 ng/ the more lipid-soluble compounds (e.g., fentanyl) act more rapidly than morphine after subcutaneous administration because of differences in the rates of absorption and entry into the CNS. Compared with more lipid-soluble opioids such as codeine, heroin, and methadone, morphine crosses the blood-brain barrier at a considerably lower rate. METABOLISM:With chronic administration, the 6-glucuronide accounts for a significant portion of morphine's analgesic actions (Osborne et al., 1988). Indeed, with chronic oral dosing, the blood levels of morphine-6-glucuronide typically exceed those of morphine. Given its greater MOR potency and its higher concentration, morphine-6-glucuronide may be responsible for most of morphine's analgesic activity in patients receiving chronic oral morphine. Morphine-6-glucuronide is excreted by the kidney.
- Developed in Germany in 1916 Designed to be a better medication than other opiates. Wasn’t supposed to be habit-forming First came to the U.S. in 1939 Became widely used when Purdue Pharma started manufacturing it in 1996 By 2001 it was the best selling narcotic pain reliever Those with the extra prescriptions started to resell the drug Started prescription drug abuse that is still a problem today Made using thebaine Still is supposed to be used to relieve pain
- Rigidity can be treated with depolarizing or non-depolarizing neuromuscular blocking agents . As with analgesia, respiratory depression after small doses is of shorter duration than with morphine but of similar duration after large doses or long infusions delayed respiratory depression also can be seen after the use of f possibly owing to enterohepatic circulation.
- is. Recovery from analgesic effects also occurs more quickly. However, with larger doses or prolonged infusions, the effects of these drugs become more lasting, with durations of action becoming similar to those of longer-acting opioids (described later). Intravenous use of fentanyl and sufentanil for postoperative pain has been popular A combination of epidural opioids with local anesthetics permits reduction in the dosage of both components, minimizing the side effects of the local anesthetic (i.e., motor blockade) and the opioid (i.e., urinary retention, itching, and delayed respiratory depression in the case of morphine). An important caveat to their spinal use is that because of their rapid clearance, these agents at analgesic spinal doses can produce blood levels that are similar to those producing effects after systemic administration (Bernards, 2004). The development of novel, minimally invasive routes of administration for fentanyl has facilitated the use of these compounds in chronic pain management Longer neurosurgical procedures Postprocedural analgesia- remifentanil + longer-acting opioid or another analgesic modality is combined
- The fentanyl HCl iontophoretic transdermal system (fentanyl ITS) is a novel patient-controlled analgesia (PCA) system that has been approved in the USA and Europe for the management of acute, moderate-to-severe postoperative pain. This system extends the applicability of transdermal drug delivery to acute pain management, allowing patients to self-administer pre-programmed doses of fentanyl non-invasively through the use of iontophoretic technology. Iontophoresis is the process by which an electric current is used to drive ionized drug molecules across the skin and into the systemic circulation. Its method of drug delivery avoids the risk of complications from needle-related injuries and infection, and its pre-programmed electronics eliminate the potential for manual programming errors and excessive dosing. because of its formulation with glycine, an inhibitory transmitter in the spinal dorsal horn longer neurosurgical procedures, where rapid emergence from anesthesia may be important.
- Meperidine C/I in patients receiving MAO inhibitors as it precipitate a syndrome characterised by muscle rigidity, hyperpyrexia & seizures. Meperidine, 25 to 50 mg, is used frequently with antihistamines, corticosteroids, acetaminophen, or nonsteroidal antiinflammatory drugs (NSAIDs) to prevent or ameliorate infusion-related rigors and shaking chills that accompany the intravenous administration of amphotericin B, aldesleukin (interleukin-2), trastuzumab, and alemtuzumab. Diphenoxylate: Its only approved use is in the treatment of diarrhea. Diphenoxylate hydrochloride is available only in combination with atropine sulfate .The recommended daily dosage of diphenoxylate for the treatment of diarrhea in adults is 20 mg in divided doses. Loperamide. It slows gastrointestinal motility by effects on the circular and longitudinal muscles of the intestine presumably as a result of its interactions with opioid receptors in the intestine. loperamide is as effective as diphenoxylate METHADONE 2.5-10 mg repeated every 8-12 hours Tab/IM/SC.
- the potential misuse of tablets as a source of injectable pentazocine by producing undesirable effects in subjects dependent on opioids.
- Noradrenergic and serotonergic neurons originate in the brainstem and terminate in the dorsal horn of the spinal cord Monoaminergic pathway modulates the spinal processing of nociception through the section of norepinephrine and serotonin Tramadol’s novel mechanism of analgesic action is partially due to its adrenergic action and Enhanced secretion of serotonin and inhibits the reuptake of serotonin in the CNS by tramadol Tramadol is a racemic mixture of a (+)- and a (-)-enantiomer. + enantiomer is selective agonist of mu-opiate receptors and preferentially inhibits serotonin reuptake. -ve enantiomer mainly inhibits noradrenaline reuptake The parent molecule also produced analgesia via a monoaminergic action
- hallucinations, paranoia, extreme anxiety, panic attacks, confusion, and unusual sensory experiences can occur in rare cases Minor possibility of this exists with both tramadol and tapentadol Avoid concurrent administration of SSRI’s or selective-norepinephrine reuptake inhibitors, triptans, or tricyclic antidepressants
- The drug undergoes extensive first pass hepatic metabolism about 97%.3 A small amount of TPA is metabolized by phase I pathways while mainly metabolized via phase II pathways.7 Hydroxylation and N-demethylation play a minor role in the metabolic fate of TAP, which forms hydroxyl tapentadol (29) and N-desmethyl tapentadol (25), respectivel The mu-receptors are present in periaqueductal gray region, superficial dorsal horn of the spinal cord, and several layers of cerebral cortex. Norepinephrine (noradrenaline) is involved with descending modulation of pain (Fig 4).1 Tapentadol is a centrally-acting synthetic analgesic which acts as mu-opioid receptor agonist as well as norepinephrine re-uptake inhibitor (NRI).2 It modifies sensory and affective aspects of pain through mu-opioid agonistic action, inhibits the transmission of pain at the spinal cord and affects the activity of pain perception. It increases the level of norepinephrine in the brain by inhibiting its re-absorption into nerve cells at the central nervous system sites, which leads to analgesia (Fig. 4).1,3,27 This combination of complementary mechanisms of action additively or synergistically results in potent analgesic activity similar to potent narcotic analgesics without their side effects
- except that the syndrome appears within minutes of administration and subsides in about 2 hours.
- The relief produced by intravenous morphine in dyspnea from pulmonary edema associated with left ventricular failure is remarkable. Proposed mechanisms include reduced anxiety (perception of shortness of breath), and reduced cardiac preload (reduced venous tone) and afterload (decreased peripheral resistance). Morphine can be particularly useful when treating painful myocardial ischemia with pulmonary edema.
- inadequate analgesia would result from oral analgesia or intermittent IV morphine boluses. One hr max dose Max amount of drug that PCA pump will deliver in 1 hour Continuous infusion Morphine 0.075 mg/kg lbw Fentanyl 0.75 mcg/kg lbw
- A number of factors may alter a patient's sensitivity to opioid analgesics
- Memantine and Mg2+ occupy the same N-methyl-D-aspartate receptor channel and are mutually exclusive. • Unlike Mg2+, memantine does not leave the channel so easily. • Block of N-methyl-D-aspartate receptor channels is partial and 15% to 20% of the channels unblock in the absence of an agonist and are available for subsequent physiological activation. • Increases brain-derived neurotrophic factor levels in the limbic cortex.
- when using opioid infusions alone would result in inadequate analgesia or to minimise opioid tolerance when prolonged opioid administration is anticipated. MOA:Strong pain stimuli activate NMDA receptors and produce hyperexcitability of dorsal root neurons. This induces central sensitization, wind-up phenomenon, and pain memory. Ketamine is supplied as a mixture of the R+ and S- isomers even though the S- isomer is more potent with fewer side effects. Paracetamol, opioids, local anaesthetics, tramadol and NSAIDs may be used concurrently with ketamine infusions improve analgesia and reduce side effects.